7-(2-Thioxo-4-thiazolidinecarboxamido)cephalosporanic acids and the corresponding S-ethers

ABSTRACT

R3 is -H, an alkali metal or -NH4; and N IS 0 OR 1. The antibacterial agents of the invention present the formula:   WHEREIN R1 is hydrogen or alkyl of 1 to 4 carbon atoms; R2 is -H, CH3CO2-,   or when taken with the 3-carboxyl group,     D R A W I N G

United States Patent [1 1 Teller et al.

[451 Sept. 23, 1975 7-(2-THIOXO-4- THIAZOLIDINECARBOXAMIDO)CEPH-ALOSPORANIC ACIDS AND THE CORRESPONDING S-ETHERS [75] Inventors: DanielM. Teller, Devon; John H.-

Sellstedt, Pottstown, both of Pa.

[73] Assignee: American Home Products Corporation, New York, NY.

[22] Filed: Feb. 22, 1974 11 App]. No.: 444,944

[52] US. Cl. 260/243 C; 424/246 [51] Int. Cl. C07D 501/20 [58] Field ofSearch 260/243 C [56] References Cited UNITED STATES PATENTS 3,813,3855/1974 Henniger et al. 260/243 C 3,840,556 10/1974 Kukolja 3,842,077lO/l974 Henniger et al. 260/243 C Primary Examiner-Nicholas S. RizzoAttorney, Agent, or Firm-Richard K. Jackson [5 7 ABSTRACT Theantibacterial agents of the invention present the formula:

R is hydrogen or alkyl of 1 to 4 carbon atoms; R is H, CH CO or whentaken with the 3-carboxyl group,

R is H, an alkali metal or NH.,; and n is 0 or 1.

3 Claims, N0 Drawings 1 2 7-(2-THIOXO-4-THIAZOLIDINECARBOXAMIDO)CEPl-IALOSPO- and RANIC ACIDS AND THECORRESPONDING S-ETl-[ERS and R is H, Na, K or NH.,. 7 The compounds ofthis invention are prepared by re- DESCRIPTION OF THE INVENTION actingthe Compounds In accordance with this invention there is providedchemical compounds of the formula: TCO H CONH l l '(R 2 H R n 1 with theappropriate 7-amino cephalosporin derivative 11 in the presence of acondensing agent such as carbonyl diimidazole, dicyclohexylcarbodiimidealone or in the R is hydrogen or alkyl or 1 to 4 carbon atoms; Presenceof N-hydl'oxysuccinimide is CH3CQ2 hydroxybenzotriazole,isobutylchloroformate, and the like. Other applicable condensing agentsare disclosed N; N by Spencer et al., J. Med. Chem., 9, pp. 746750 l l(1966), Micetich et al., J. Med. Chem., 15, pp. S LS 3 S 333-335 (1972);Klausner et al., Synthesis. pp.

453-463 (1972) and US. Pat. No. 3,338,896.

Alternatively, the precursor carboxylic acid may be converted to an acidhalide by known means and used in aqueous medium to acylate the free7-amino group or when taken with the 3'carb0xyl rou of either an alkalimetal salt or ammonium salt of the desired cephalosporanic acidreactant. Likewise, the

acid halide may be used to acylate, in organic solution,

either a tertiary amine salt or a silylated, phosphory- 5 lated orsaccharinated derivative of the 7-amino cephalosporin derivative.

The precursor thiazole and thiazolidine carboxylic acids were preparedby the following methods: R is -H, an alkali metal or NH,; n is 0 or 1;and

the dotted lines represent the Presence of a double (1) HS CH2CHCO2H CS2MOH bond to form the thiazole and thiazolidine hetero- 2) HCI cyclicring structure depending upon the value of 40 NH2 N n. A preferred groupof compounds from the stand- \I/ point of ease of production of thestarting materials and the final products are those of the formula:

R'X CONH ;--N H R O s N S CO R wherein the first step of the reactionfollowing the procedure of R is H, CH;,CO or US. Pat. No. 3,697,516;

OH (2) NH CH CN CS CH0 CH0 COH +KOH- -g FT S SH where the alkyl halideRX is l-, Bror CI-.

The reaction sequence being that disclosed by Doyle et al., J. Chem.Soc. (London), pp. 4605-4614 (1958) and Cook et al., J. Chem. Soc.(London), pp. 201-206 (1948).

The compounds of this invention have been found to be activeantibacterials effective against gram-positive and gram-negative testorganisms as well as penicillin resistant staphlococcus by using thewell known and scientificially accepted agar serial dilution testingtechnique. Thus, the compounds of the invention are useful in the fieldsofcomparative pharmacology and in microbiology and may be used for thetreatment of infections amenable to treatment with cephalosporinantibiotics. i

The following examples illustrate the preparation of the cephalosporinderivatives of this invention, employing2-thioxo-4-thiazolidinecarboxylic acid as representative of the group ofacyl reactants disclosed above and -7-aminocephalosporanic acid asrepresentative of the otherwise known -7-aminocephalosporin reactantsembraced by the structural formula presented, supra. The activitiy ofthe products of the examples is pres: ented for those specific bacterialstrains against which the compound exemplified was active at or below250 micrograms per milliliter. The representative nature of thebacterial strains employed to demonstrate antibacterial activity areindicative of the broaderapplicability of the compounds of thisinvention in the control of bacterial infestations other than thosespecifically referred to in each of the following examples. The bacteriaare named-followed by the specific strain and the concentration inmicrograms per milliliter at which 100 percent inhibition occurred. Theabbreviations for each bacterium are:

Ba Su Bacillus subtilis St Au Staphylococcus aureus Ne Ca Neisseriacatarrhalis Es Co Escherichia coli Es In Escherichia intermedia Sa PaSalmonella paratyphi Sa Ty Salmonella typhosa Kl Pn Klebsiellapneumoniae Bo Br Bordetella bronchiseptica Pr Vu Proteus vulgaris St PyStaphylococcus pyrogenes Pr My Proteus myrablis He Sp HereIlea speciesThe in .vivo data was obtained by injecting mice (male, 16-18 grams MBRstrain) intraperitoneally with 0.5 milliliters of a suspension of theinfective agent in 5 percent gastric mucin. The animals were randomizedand treated with the cephalosporin derivative subcutaneously from 0.5 to1 hour after randomization. A second dose was administered 6 hourslater. Twenty-four hours post-infection, all surviving animals receiveda final dose of thc compoundbeing tested. ln each trial, injectedcontrols'amounted to at least 10 percent of the infected pooled mice.All the animals were observed for a period of 14 days and the CD(curative dose) values were determined by the method of Reed and Muench(1958).

1 EXAMPLE 1 7-( 2-Thioxo-4-thiazolidinecarboxamido )cephalosporanicacid.

To a solution of 2-thioxo-4-thiazolidinecarboxylic acid (0.82 g, 0.0050moles) in dry dimethylformamide (10 milliliters) at room temperature isadded carbonyl diimidazole 0.82 g. 0.0050 moles) under. nitrogen. Carbondioxide evolution begins immediately with formation of a precipitate.After 30 minutes at room temperature, the residual carbon dioxide isremoved under vacuum. The mixture is cooled to about 10C. and a solutionof 7-aminoc'ephalosporanic acid 1.36 grams, 0.005 moles) in drymethylene chloride (20 milliliters) containing triethylamine (2.08milliliters) is added all at once. After stirring 2 hours at roomtemperature, the mixture is concentrated at 40C. in vacuo. n-Butanol(5.0 milliliters) is added, then potassium ethyl hexanoate (2.50milliliters of 2 Molar solution in n-butanol). After stirring 10minutes, diethyl ether milliliters) is added and the product filtered,2.50 grams of yellow solid; m.p. -147C. (decomposition). The product ispurified by dissolving in water (400 milliliters), wash- Amax 5.60,5.78, 5.85 (shoulder), 5.90 a (shoulder);

N MR has 2.05 ppm peak.

Elemental Analysis for: C H N O S Calcd: C, 40.29; H, 3.63; N, 10.07; S,23.04. Foundi C, 40.69; H, 4.22; N, 8.67; S, 25.09.-

Ba Su 6633 v 0.122 St Au 6538P 0.488 St Au Smith 0.488 St Au CHP v1.95St Au 53-180 0.976 Ne Ca 8193 31.3 Es Co 9637 15.6 Es ln 65-l 250 Sa Pa1 1737 7.81 Kl Pn I003] 7.8l Bo Br 4617 62.5

Pr Vu 6896 The in vivo data is as follows:

Organism Strain Curative Dose 50 in' milligrams per mouse s Py c2031.13;!19 Pr My PR3 v 2.68; 4.9

SAD12 7.2

Sa Ty EXAMPLE n The process of the preceding example was repeatedemploying five times as much of the reactants, to ob tain 4.7 grams ofyellow solid, mp. 110-l40C. (decomposition) with an identical infra redand NMR spectrum and Elemental Analysis for: C H, N O S Calcd: C, 40.29;H, 3.63; N, 10.07; S, 23.04. Found: C, 40.51; H, 4.09; N, 9.86; S,23.13.

B21 Su 6633 0.122 St Au 6538P 0488 St Au SMITH 0.488 St Au CHP 1.95 StAu 53-180 1.95 Es Co 9637 3.90 Sa Pa 11737 3.90 Kl Pn 10031 3.90 Pr Vu6896 125 Es ln 65-1 250 He Sp 9955 250 Ne C2: 8193 62.5

Bo Br I 4617 62.5

What is claimed is: l. A compound of the formula:

R is hydrogen or alkyl of 1 to 4 carbon atoms;

R is hydrogen, acetoxy or N-pyridinium R is hydrogen, an alkali metal orthe ammonium ion;

and

n is 0 or 1.

2. A compound of claim 1 of the formula:

s i l c R2 m H2 wherein R is hydrogen, acetoxy or N-pyridinium; and R ishydrogen, sodium, potassium or the ammonium ion. 3. The compound ofclaim 1 which is 7 2-thioxo-4- 4Othiazolidine-carboxamido)cephalosporanic acid.

1. A COMPOUND OF THE FORMULA:
 2. A compound of claim 1 of the formula:3. The compound of claim 1 which is7-(2-thioxo-4-thiazolidine-carboxamido)cephalosporanic acid.